Multi-modal antidepressant-like action of 6- and 7-chloro-2-aminodihydroquinazolines in the mouse tail suspension test

Rationale: 2-Amino-6-chloro-3,4-dihydroquinazoline (e.g., A6CDQ) represents a novel putative antidepressant originally thought to act through a 5-HT₃ serotonin receptor antagonist mechanism. Here, we investigated this further by examining a positional isomer of A6CDQ (i.e., A7CDQ). Materials and methods: 5-HT₃ receptor and transporter activity (uptake-1 and uptake-2) were investigated using a variety of in vitro assays and the in vivo mouse tail suspension test (TST). Results: Although A7CDQ binds at 5-HT₃ receptors with low affinity (K_i = 1975 nM) compared to A6CDQ (K_i = 80 nM), it retained 5-HT₃ receptor antagonist action (IC₅₀ = 5.77 and 0.26 μM, respectively). In the mouse TST A7CDQ produced antidepressant-like actions (ED₅₀ = 0.09 mg/kg) comparable to that of A6CDQ. In addition, A6CDQ was found to be a 5-HT releasing agent (K_m = 2.8 μM) at hSERT and a reuptake inhibitor (IC₅₀ = 1.8 μM) at hNET, whereas A7CDQ was a weak reuptake inhibitor (K_m = 43.6 μM) at SERT but a releasing agent (EC₅₀ = 3.3 μM) at hNET. Moreover, A6CDQ and A7CDQ were potent inhibitors of uptake-2 (e.g.; OCT3 IC₅₀ = 3.9 and 5.9 μM, respectively). Conclusions: A simple shift of a substituent in a common quinazoline scaffold from one position to another (i.e., a chloro group from the 6- to the 7-position) resulted in a common action in the TST but via a somewhat different mechanism. A6CDQ and A7CDQ might represent the first members of a new class of potential antidepressants with a unique multi-modal mechanism of action.